Infections caused by HIV-1 and Mycobacterium tuberculosis are each regarded as global public health crises. In the central nervous system, these agents cause two of the most devastating infectious diseases. It is also well recognized that microglial cells play a pivotal role in the neuropathogenesis of HIV-1 and M. tuberculosis and that drugs of abuse not only contribute to the spread of these agents but may facilitate their expression in microglial cells. Despite considerable research on the effects of psychoactive drugs such as cocaine and opiates on microglial cells, little or nothing is known about the effect of nicotine, which is extensively used by drug-dependent individuals, on the neuropathogenesis of either of these infectious agents. The intent of this research project is to improve understanding of the manner by which nicotine, which is known to have immunomodulatory activities, may affect neuropathogenic mechanisms of HIV-1 and M. tuberculosis. The principal hypothesis to be tested in this research project is that nicotine enhances neuropathogenic mechanisms of HIV-1 and M. tuberculosis through its effects on microglial cells. We have focused on two critical aspects of HIV-1 and M. tuberculosis neuropathogenesis: replication within microglia and induction of cytokines and chemokines in response to HIV-1 proteins gp41 and Tat and M. tuberculosis. To test this hypothesis, we will conduct experiments using primary human microglial cells in culture and various methodologies, including microarray techniques, to assess nicotine's effect on the interactions of these infectious agents with microglia. Major emphasis will be placed on defining the mechanisms whereby nicotine enhances the neuropathogenic processes of each of these pathogens. Along with carrying out the proposed studies of the effects of nicotine on targeted functional and genomic responses of microglia, intensive training will be undertaken by the principal investigator during the course of this research project both in the fields of molecular genetics and molecular epidemiology. This training will prepare the principal investigator as a physician scientist for a career devoted to investigation of the potential impact of psychoactive substances on host-microbe interactions at the molecular/cellular, individual and population levels.